Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zygomycoses are rare invasive mould infections which mainly occur in immunocompromised patients, especially during prolonged neutropenia. The high mortality rate is due to a high failure rate of both intravital diagnosis and treatment. Exact diagnosis requires microscopic examination and proof by culture. The treatment consists of amphotericin B and surgical debridement. We report four recent cases of zygomycosis among 89 patients with intensively treated acute leukaemia at our institution. Three cases were breakthrough infections since the patients were under voriconazole treatment prior to diagnosis of zygomycosis. Only one patient had premortal diagnosis (paranasal sinus infection) and showed clinical response with amphotericin B and surgical debridement. A review of the literature of these emerging fungal infections is given and is focused on patients with acute leukaemia. In addition, the importance of autopsy as a tool for quality control and epidemiological studies is pointed out.
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PMID:Zygomycoses in patients with acute leukaemia. 1652 12

We evaluated autopsy-proven invasive fungal infections (IFI) in patients with hematologic malignancies over three periods (1989-1993, 1994-1998, and 1999-2003). The autopsy rate declined significantly (67%-34%-26%, respectively p<0.0001). IFI were identified in 314 (31%) of 1017 autopsies. Most IFI (75%) were not diagnosed antemortem. The prevalence of invasive mold infections increased significantly (19%-24%-25% p=0.05) in parallel with the emergence of Zygomycetes (0.9%-4%-3%; p=0.03). The prevalence of all other IFI remained relatively constant. Among patients with invasive pulmonary aspergillosis, those with graft-versus-host disease had a histopathological pattern distinct from those with neutropenia. The complex and evolving epidemiology of IFI in severely immunocompromised patients is not well captured by current diagnostic methods.
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PMID:Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003). 1675 15

Fungi are increasingly recognised as major pathogens in critically ill patients. Candida spp. and Cryptococcus spp. are the yeasts most frequently isolated in clinical practice. The most frequent filamentous fungi (moulds) isolated are Aspergillus spp., but Fusarium spp., Scedosporium spp., Penicillium spp., and Zygomycetes are increasingly seen. Several reasons have been proposed for the increase in invasive fungal infections, including the use of antineoplastic and immunosuppressive agents, broad-spectrum antibiotics, and prosthetic devices and grafts, and more aggressive surgery. Patients with burns, neutropenia, HIV infection and pancreatitis are also predisposed to fungal infection. The epidemiology and clinical features of fungal infections are reviewed, together with antifungal agents currently or soon to be available.
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PMID:Invasive fungal infections: a review of epidemiology and management options. 1677 6

This study reviewed retrospectively the clinical characteristics of 28 cancer patients with fungal osteoarticular infections (FOAIs) between 1995 and 2005. Most patients (26; 93%) had haematological malignancies (19 had leukaemia); half (14) were allogeneic stem-cell transplant recipients. Twelve patients (43%) had severe neutropenia (< or = 100/mm3) with a mean duration of 65 days (range 10-500 days), and ten (36%) patients had received a significant dose of corticosteroids. Most (19; 68%) FOAIs were caused by contiguous extension, while nine (32%) were associated with haematogenous spread. Pain, joint instability and local drainage were seen in 28 (100%), six (21%), and seven (25%) patients, respectively. Sixteen (57%) patients had symptoms for < 1 month. The sinuses (ten; 36%) and the vertebral spine (six; 21%) were the most common sites involved. Moulds were the predominant pathogens: Aspergillus fumigatus (two); non-fumigatus Aspergillus spp. (eight); non-specified Aspergillus spp. (three); Fusarium spp. (six); Zygomycetes (five); Scedosporium apiospermum (two); and Exserohilum sp. (one). Candida was the causative pathogen in four cases (including two cases of mixed FOAIs). Arthritis and post-operative FOAIs were both uncommon manifestations, occurring in two patients each. All patients received systemic antifungal therapy (combinations in 20 cases), and 19 cases underwent adjunctive surgery. The crude mortality rates (at 12 weeks) were 44% (9/20) in the patients who underwent surgery and antifungal therapy vs. 33% (2/6) in patients who received antifungal therapy alone (p not significant). FOAI is a rare, yet severe, manifestation of localised or systemic mycoses, caused predominantly by moulds, and is seen typically in patients with haematological malignancies.
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PMID:Fungal osteoarticular infections in patients treated at a comprehensive cancer centre: a 10-year retrospective review. 1677 57

Invasive fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. In particular, patients with neutropenia and those who have undergone allogeneic hematopoietic stem cell transplantation are at highest risk, with fungal pneumonia being the main clinical manifestation in these patients. The most common pathogens associated with fungal pneumonia are Aspergillus spp. and Zygomycetes. However, other pathogens have also been observed in fungal pneumonia, including Cryptococcus spp., Pneumocystis jirovecii, and Candida spp. This comprehensive review will focus on the important practical aspects relevant to the epidemiology, clinical diagnosis, and therapeutic management of pneumonia due to filamentous fungi in patients affected by hematological malignancies.
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PMID:Fungal pneumonia due to molds in patients with hematological malignancies. 1702 88

Zygomycosis in patients with persistent neutropenia had been associated with poor outcomes despite aggressive surgical and antifungal therapy. We describe the case of a 10-year-old girl with aplastic anaemia and persistent neutropenia who developed cutaneous and subcutaneous zygomycosis of her right thigh that was successfully treated with extensive surgical debridement, intravenous liposomal amphotericin B, later changed to oral posaconazole for long-term suppressive therapy and granulocyte colony stimulating factor.
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PMID:Successful treatment of cutaneous and subcutaneous zygomycosis in an immunosuppressed patient with aplastic anaemia. 1720 64

Posaconazole is a new drug in the triazole class that has recently been investigated in pivotal Phase III clinical trials. Its antifungal activity is based on the inhibition of the fungal ergosterol synthesis. As demonstrated in vitro, posaconazole exhibits fungicidal activity against Aspergillus spp., Candida spp. and zygomycetes. Currently, posaconazole is only available as an oral suspension. Food consumption affects the bioavailability of posaconazole, while the exposure to posaconazole increases in a dose-proportional manner with a saturation of absorption occurring with a daily dose over 800 mg. Posaconazole is well tolerated without an increase in risk of any treatment-related adverse events during prolonged treatment for 6 or more months (n = 108). Posaconazole has been recently approved by the US FDA and other regulatory bodies for the treatment of oropharyngeal candidiasis, and the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients. As demonstrated in two pivotal Phase III trials, posaconazole prophylaxis of invasive fungal infection in patients severely immunocompromised by graft-versus-host disease (n = 600) or neutropenia (n = 602) is superior to fluconazole and/or itraconazole prophylaxis. Significantly more patients who received posaconazole, instead of fluconazole, as treatment for oropharyngeal candidiasis sustained clinical success after the treatment was stopped. Preliminary data from a subgroup analysis (n = 24) of two salvage therapy trials for invasive fungal infections, as well as single case reports and series and in vitro studies, suggest that posaconazole might be an attractive oral treatment alternative for zygomycosis.
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PMID:Posaconazole: a next-generation triazole antifungal. 1766 96

Posaconazole is a triazole antifungal agent with a spectrum of activity that includes Candida and Cryptococcus species, many molds, and some endemic fungi. Posaconazole has received US Food and Drug Administration approval for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole. It is also approved as prophylaxis for invasive Aspergillus and Candida infections in patients aged >or=13 years who are at high risk of developing these infections, in adult and adolescent hematopoietic stem cell transplant recipients with graft-versus-host disease, and in persons with hematologic malignancies and prolonged neutropenia due to chemotherapy, who are at high risk of developing these infections. Approval for additional indications is being sought. Limited clinical experience suggests efficacy for the treatment of infections due to Zygomycetes and as salvage therapy for patients with invasive aspergillosis and coccidioidomycosis. Currently available only as an oral suspension, posaconazole, which has been well tolerated, requires administration with food or a nutritional supplement to assure adequate bioavailability. Posaconazole is predominantly eliminated in the feces, where it appears as unchanged drug. Metabolism, mostly glucuronidation, plays only a minor role in its elimination, as does renal clearance; as a consequence, dose adjustment is not required in the presence of renal or hepatic insufficiency. Although not a substrate of hepatic CYP450 3A4, posaconazole inhibits this enzyme and thus has the potential for significant pharmacokinetic interactions with drugs metabolized by this isoform. Its use in combination with CYP450 substrates that prolong the QTc interval is contraindicated, as is its use with ergot alkaloids; administration of posaconazole with other substrates and/or inducers of this enzyme system requires caution. Posaconazole is both a substrate and inhibitor of P-glycoprotein. Currently, the major roles for posaconazole in clinical practice are as prophylaxis for neutropenic patients with significant risk of infection with filamentous fungi and as therapy for zygomycoses. It may also have a role in the treatment of other filamentous fungal and some yeast infections, but assessment of its overall place in antifungal therapy awaits the availability of further clinical experience.
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PMID:Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. 1841 3

Zygomycosis has emerged as an increasingly common infection in immunocompromised patients. Although the majority of these cases are community acquired, hospital outbreaks have been described, linked to the use of contaminated products. Risk factors for development of zygomycosis include uncontrolled diabetes mellitus, neutropenia, use of immunosuppressive medications, and iron overload states. Recent studies have shown the central role of iron in the pathogenesis of zygomycosis and the effect of disease states such as ketoacidosis and hyperglycemia on the availability of iron to the Zygomycetes. These organisms most commonly infect the sinuses, lungs, central nervous system, and skin and soft tissues. Diagnosis often involves invasive procedures, including deep tissue biopsy, because radiological studies are not specific for this disease, and other less invasive diagnostic modalities have not yet been proven to be sensitive or specific. Treatment may require a combined medical and surgical approach in these frequently frail patients; yet, even with such aggressive measures the mortality of zygomycosis remains high.
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PMID:Pulmonary zygomycosis. 1836 93

Although our antifungal armamentarium has been enlarged recently with new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin, anidulafungin), the polyenes still have an important role in antifungal strategies because of their extended antifungal spectrum and rarity of mycological resistance. The use of conventional amphotericin B deoxycholate is limited by substantial toxicity that is either infusion-related or associated with renal failure. Its lipid derivatives, particularly liposomal amphotericin B (LAmB), are less nephrotoxic while maintaining a broad antifungal spectrum. LAmB is active against most Candida spp., including Candida glabrata and Candida parapsilosis, and against more resistant, emerging yeasts species such as Rhodotorula spp., Geotrichum spp. and Trichosporon spp.. LAmB is also active against Cryptococcus spp. and all dimorphic fungi such as Histoplasma, Blastomyces, Coccidioidomyces, and Paracoccidiodomyces. The antifungal spectrum of LAmB is particularly interesting with regard to filamentous fungi, with marked activity against Aspergillus spp. and agents of zygomycosis. The latter might emerge during long-term treatment with voriconazole or an echinocandin, as these organisms are resistant to these drugs. We review here the role of LAmB in the current antifungal management strategy, which is based on results obtained in prospective trials. LAmB can be retained as first-line treatment for human immunodeficiency virus (HIV)-positive patients with disseminated histoplasmosis and cryptococcosis, even in the setting of renal impairment or concomitant administration of potentially nephrotoxic drugs. In addition, there is sufficient evidence that the drug should be a major consideration for the empirical treatment of persistent febrile neutropenia or as an alternative to for patients with invasive aspergillosis, for those at risk of renal impairment, major drug-drug interaction or liver insufficiency, particularly in the situation of an established azole intolerance. The primary licensed indication for LAmB is empirical treatment. When zygomycosis is suspected or has been documented, high doses of LAmB should be prescribed. Finally, LAmB may also be considered as a therapeutic option for the management of candidaemia and remains a cornerstone for the treatment of some visceral localisations during systemic candidosis.
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PMID:Liposomal amphotericin B: what is its role in 2008? 1843 Jan 32


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